1. Field of the Invention
This invention relates to the preparation by fermentation of a known compound, 3,7-dihydroxytropolone, which has previously been produced only by chemical synthesis.
The invention also relates to the novel discovery that 3,7-dihydroxytropolone inhibits the growth of mammalian tumors and can be used as an antitumor agent for treatment of such tumors.
2. Description of the Prior Art
3,7-Dihydroxytropolone is a known compound which has previously been prepared by chemical synthesis. Nozoe, et. al. in Bull. Chem. Soc. Japan 33: 1071, 1960 describe synthesis of 3,7-dihydroxytropolone by heating 3,7-dibromotropolone with sodium .beta.-naphthalenesulfonate in dilute alkaline solution. Kirst, et. al. in J. Antibiotics 35 (12): 1651-1657, 1982 disclose synthesis of 3,7-dihydroxytropolone along with 7-hydroxytropolone, 5-hydroxytropolone and 4,7-dihydroxytropolone by persulfate oxidation of tropolone. The Kirst paper indicates that 3,7-dihydroxytropolone possesses antimicrobial activity. Applicants are unaware, however, of any disclosure that 3,7-dihydroxytropolone or its analogs (e.g. 7-hydroxytropolone, 5-hydroxytropolone or 4,7-dihydroxytropolone) possess antitumor activity.
Several natural and synthetic tropolones have been reported in the literature to have antitumor activity. Illustrative of such antitumor tropolone derivatives are those described in Japanese Published Applications 59/134,720, 59/134,744, 59/134,745, 54/61,158, 63/25,393, 63/25,367 and Canadian Pat. No. 787,451. See also, J. Med. Chem. 28(8): 1026-1031, 1985, J. Med. Chem. 27(12): 1749- 1753, 1984, Chem. Pharm. Bull. (Tokyo) 31(8): 2952-1954, 1983, Boll. Soc. Ital. Biol. Sper. 43(1): 14-17, 1967, Nippon Yakurigaku Zasshi 60: 52-61, 1964, Nippon Yakurigaku Zasshi 55: 1061-1064, 1959, J. Med. Chem. 24: 251-256, 1981 and J. Med. Chem. 26: 1365-1369, 1983.
Japanese Published Application 60/228414 discloses tropolone derivatives of the formula ##STR2## where R.sub.3 -R.sub.7 .dbd.H.sub.1, lower alkyl, OH, NH.sub.2, lower alkoxy, halogen, mono- or di-lower alkylamino, COOH or lower alkyloxycarbonyl as being useful for treatment of arteriosclerosis or inflammation. 3,7-Dihydroxytropolone is generically encompassed by the disclosure.
Despite the extensive search for antitumor derivatives of tropolone, there has been no disclosure, as mentioned above, that 3,7-dihydroxytropolone possesses any antitumor activity.